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. 1999 Feb 15;338(Pt 1):35–39.

Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling.

R Zhao 1, Z J Zhao 1
PMCID: PMC1220021  PMID: 9931295

Abstract

SHP-2 is a widely distributed Src homology 2 (SH2) domain-containing tyrosine phosphatase that is recruited to growth factor receptors on stimulation. We have transiently co-expressed several catalytically active and inactive forms of the enzyme with the platelet-derived growth factor (PDGF) receptor in human embryonic kidney 293 cells. The catalytically active forms of SHP-2 decreased the tyrosine phosphorylation of the receptor, whereas the catalytically inactive forms increased the phosphorylation. However, PDGF-induced activation of the mitogen-activated protein (MAP) kinase pathway was enhanced by the active forms of SHP-2 but decreased by the inactive forms. The results suggest that the PDGF receptor is a physiological substrate of SHP-2 and that SHP-2 has a positive role in the PDGF-stimulated activation of MAP kinase. The dissociation of the receptor phosphorylation from the activation of MAP kinase suggests that signalling through growth factor receptors does not depend merely on their tyrosine phosphorylation.

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Selected References

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  1. Adachi M., Fischer E. H., Ihle J., Imai K., Jirik F., Neel B., Pawson T., Shen S., Thomas M., Ullrich A. Mammalian SH2-containing protein tyrosine phosphatases. Cell. 1996 Apr 5;85(1):15–15. doi: 10.1016/s0092-8674(00)81077-6. [DOI] [PubMed] [Google Scholar]
  2. Bennett A. M., Hausdorff S. F., O'Reilly A. M., Freeman R. M., Neel B. G. Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol Cell Biol. 1996 Mar;16(3):1189–1202. doi: 10.1128/mcb.16.3.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bouchard P., Zhao Z., Banville D., Dumas F., Fischer E. H., Shen S. H. Phosphorylation and identification of a major tyrosine phosphorylation site in protein tyrosine phosphatase 1C. J Biol Chem. 1994 Jul 29;269(30):19585–19589. [PubMed] [Google Scholar]
  4. Case R. D., Piccione E., Wolf G., Benett A. M., Lechleider R. J., Neel B. G., Shoelson S. E. SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides. J Biol Chem. 1994 Apr 8;269(14):10467–10474. [PubMed] [Google Scholar]
  5. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Claesson-Welsh L. Platelet-derived growth factor receptor signals. J Biol Chem. 1994 Dec 23;269(51):32023–32026. [PubMed] [Google Scholar]
  7. David M., Zhou G., Pine R., Dixon J. E., Larner A. C. The SH2 domain-containing tyrosine phosphatase PTP1D is required for interferon alpha/beta-induced gene expression. J Biol Chem. 1996 Jul 5;271(27):15862–15865. doi: 10.1074/jbc.271.27.15862. [DOI] [PubMed] [Google Scholar]
  8. Fujioka Y., Matozaki T., Noguchi T., Iwamatsu A., Yamao T., Takahashi N., Tsuda M., Takada T., Kasuga M. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol Cell Biol. 1996 Dec;16(12):6887–6899. doi: 10.1128/mcb.16.12.6887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. doi: 10.1016/0092-8674(95)90404-2. [DOI] [PubMed] [Google Scholar]
  10. Kazlauskas A., Feng G. S., Pawson T., Valius M. The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6939–6943. doi: 10.1073/pnas.90.15.6939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kharitonenkov A., Chen Z., Sures I., Wang H., Schilling J., Ullrich A. A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature. 1997 Mar 13;386(6621):181–186. doi: 10.1038/386181a0. [DOI] [PubMed] [Google Scholar]
  12. Klinghoffer R. A., Kazlauskas A. Identification of a putative Syp substrate, the PDGF beta receptor. J Biol Chem. 1995 Sep 22;270(38):22208–22217. doi: 10.1074/jbc.270.38.22208. [DOI] [PubMed] [Google Scholar]
  13. Lechleider R. J., Sugimoto S., Bennett A. M., Kashishian A. S., Cooper J. A., Shoelson S. E., Walsh C. T., Neel B. G. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. J Biol Chem. 1993 Oct 15;268(29):21478–21481. [PubMed] [Google Scholar]
  14. Leevers S. J., Paterson H. F., Marshall C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  15. Li W., Nishimura R., Kashishian A., Batzer A. G., Kim W. J., Cooper J. A., Schlessinger J. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994 Jan;14(1):509–517. doi: 10.1128/mcb.14.1.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Milarski K. L., Saltiel A. R. Expression of catalytically inactive Syp phosphatase in 3T3 cells blocks stimulation of mitogen-activated protein kinase by insulin. J Biol Chem. 1994 Aug 19;269(33):21239–21243. [PubMed] [Google Scholar]
  17. Noguchi T., Matozaki T., Horita K., Fujioka Y., Kasuga M. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 1994 Oct;14(10):6674–6682. doi: 10.1128/mcb.14.10.6674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Perkins L. A., Larsen I., Perrimon N. corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell. 1992 Jul 24;70(2):225–236. doi: 10.1016/0092-8674(92)90098-w. [DOI] [PubMed] [Google Scholar]
  19. Pluskey S., Wandless T. J., Walsh C. T., Shoelson S. E. Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains. J Biol Chem. 1995 Feb 17;270(7):2897–2900. doi: 10.1074/jbc.270.7.2897. [DOI] [PubMed] [Google Scholar]
  20. Rivard N., McKenzie F. R., Brondello J. M., Pouysségur J. The phosphotyrosine phosphatase PTP1D, but not PTP1C, is an essential mediator of fibroblast proliferation induced by tyrosine kinase and G protein-coupled receptors. J Biol Chem. 1995 May 5;270(18):11017–11024. doi: 10.1074/jbc.270.18.11017. [DOI] [PubMed] [Google Scholar]
  21. Seger R., Ahn N. G., Posada J., Munar E. S., Jensen A. M., Cooper J. A., Cobb M. H., Krebs E. G. Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells. J Biol Chem. 1992 Jul 15;267(20):14373–14381. [PubMed] [Google Scholar]
  22. Stokoe D., Macdonald S. G., Cadwallader K., Symons M., Hancock J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science. 1994 Jun 3;264(5164):1463–1467. doi: 10.1126/science.7811320. [DOI] [PubMed] [Google Scholar]
  23. Tanaka A., Gibbs C. P., Arthur R. R., Anderson S. K., Kung H. J., Fujita D. J. DNA sequence encoding the amino-terminal region of the human c-src protein: implications of sequence divergence among src-type kinase oncogenes. Mol Cell Biol. 1987 May;7(5):1978–1983. doi: 10.1128/mcb.7.5.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tang T. L., Freeman R. M., Jr, O'Reilly A. M., Neel B. G., Sokol S. Y. The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell. 1995 Feb 10;80(3):473–483. doi: 10.1016/0092-8674(95)90498-0. [DOI] [PubMed] [Google Scholar]
  25. Tomic S., Greiser U., Lammers R., Kharitonenkov A., Imyanitov E., Ullrich A., Böhmer F. D. Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C. J Biol Chem. 1995 Sep 8;270(36):21277–21284. doi: 10.1074/jbc.270.36.21277. [DOI] [PubMed] [Google Scholar]
  26. Valius M., Secrist J. P., Kazlauskas A. The GTPase-activating protein of Ras suppresses platelet-derived growth factor beta receptor signaling by silencing phospholipase C-gamma 1. Mol Cell Biol. 1995 Jun;15(6):3058–3071. doi: 10.1128/mcb.15.6.3058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Xiao S., Rose D. W., Sasaoka T., Maegawa H., Burke T. R., Jr, Roller P. P., Shoelson S. E., Olefsky J. M. Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction. J Biol Chem. 1994 Aug 19;269(33):21244–21248. [PubMed] [Google Scholar]
  28. Yamauchi K., Milarski K. L., Saltiel A. R., Pessin J. E. Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):664–668. doi: 10.1073/pnas.92.3.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yamauchi K., Ribon V., Saltiel A. R., Pessin J. E. Identification of the major SHPTP2-binding protein that is tyrosine-phosphorylated in response to insulin. J Biol Chem. 1995 Jul 28;270(30):17716–17722. doi: 10.1074/jbc.270.30.17716. [DOI] [PubMed] [Google Scholar]
  30. Zhao Z. J., Zhao R. Purification and cloning of PZR, a binding protein and putative physiological substrate of tyrosine phosphatase SHP-2. J Biol Chem. 1998 Nov 6;273(45):29367–29372. doi: 10.1074/jbc.273.45.29367. [DOI] [PubMed] [Google Scholar]
  31. Zhao Z., Larocque R., Ho W. T., Fischer E. H., Shen S. H. Purification and characterization of PTP2C, a widely distributed protein tyrosine phosphatase containing two SH2 domains. J Biol Chem. 1994 Mar 25;269(12):8780–8785. [PubMed] [Google Scholar]
  32. Zhao Z., Shen S. H., Fischer E. H. Stimulation by phospholipids of a protein-tyrosine-phosphatase containing two src homology 2 domains. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4251–4255. doi: 10.1073/pnas.90.9.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zhao Z., Tan Z., Wright J. H., Diltz C. D., Shen S. H., Krebs E. G., Fischer E. H. Altered expression of protein-tyrosine phosphatase 2C in 293 cells affects protein tyrosine phosphorylation and mitogen-activated protein kinase activation. J Biol Chem. 1995 May 19;270(20):11765–11769. doi: 10.1074/jbc.270.20.11765. [DOI] [PubMed] [Google Scholar]

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